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      Inflammaging impairs peripheral nerve maintenance and regeneration

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          Abstract

          The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo . Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti‐inflammatory therapies aiming to improve nerve regeneration in old age.

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          Most cited references24

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          Aging of the innate immune system.

          The innate immune system is composed of a network of cells including neutrophils, NK and NKT cells, monocytes/macrophages, and dendritic cells that mediate the earliest interactions with pathogens. Age-associated defects are observed in the activation of all of these cell types, linked to compromised signal transduction pathways including the Toll-like Receptors. However, aging is also characterized by a constitutive pro-inflammatory environment (inflamm-aging) with persistent low-grade innate immune activation that may augment tissue damage caused by infections in elderly individuals. Thus, immunosenescence in the innate immune system appears to reflect dysregulation, rather than exclusively impaired function. Copyright 2010. Published by Elsevier Ltd.
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            Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation

            Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both to generate and assay relevant activity. Bronchoalveolar lavage (BAL) fluid was taken from sensitized guinea pigs at intervals after aerosol challenge with ovalbumin. BAL fluid was injected intradermally in unsensitized assay guinea pigs and the accumulation of intravenously injected 111In- eosinophils was measured. Activity was detected at 30 min after allergen challenge, peaking from 3 to 6 h and declining to low levels by 24 h. 3-h BAL fluid was purified using high performance liquid chromatography techniques in conjunction with the skin assay. Microsequencing revealed a novel protein from the C-C branch of the platelet factor 4 superfamily of chemotactic cytokines. The protein, "eotaxin," exhibits homology of 53% with human MCP-1, 44% with guinea pig MCP-1, 31% with human MIP-1 alpha, and 26% with human RANTES. Laser desorption time of flight mass analysis gave four different signals (8.15, 8.38, 8.81, and 9.03 kD), probably reflecting differential O- glycosylation. Eotaxin was highly potent, inducing substantial 111In- eosinophil accumulation at a 1-2 pmol dose in the skin, but did not induce significant 111In-neutrophil accumulation. Eotaxin was a potent stimulator of both guinea pig and human eosinophils in vitro. Human recombinant RANTES, MIP-1 alpha, and MCP-1 were all inactive in inducing 111In-eosinophil accumulation in guinea pig skin; however, evidence was obtained that eotaxin shares a binding site with RANTES on guinea pig eosinophils. This is the first description of a potent eosinophil chemoattractant cytokine generated in vivo and suggests the possibility that similar molecules may be important in the human asthmatic lung.
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              Effects of low-dose aspirin on acute inflammatory responses in humans.

              Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirin(high), 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-kappaB, but is cardioprotective at lower doses (aspirin(low), 75 mg). The latter arises from the inhibition of thromboxane (Tx) B(2), a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirin(low) is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A(4) it is not known whether aspirin(low) is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirin(low) (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-kappaB-regulated gene expression and inhibition of conventional prostanoids. However, aspirin(low) triggered 15-epi-lipoxin A(4) synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A(4) exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirin(low) possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A(4) as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.
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                Author and article information

                Contributors
                helen.morrison@leibniz-fli.de
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                31 August 2018
                December 2018
                : 17
                : 6 ( doiID: 10.1111/acel.2018.17.issue-6 )
                : e12833
                Affiliations
                [ 1 ] Leibniz Institute on Aging Fritz Lipmann Institute Jena Germany
                [ 2 ] Department of Genetics and Program in Cellular Neuroscience, Neurodegeneration and Repair Yale University School of Medicine New Haven Connecticut
                [ 3 ] Institute of Anatomy University of Bonn Bonn Germany
                [ 4 ] Institute of Molecular Cell Biology Jena University Hospital Jena Germany
                Author notes
                [*] [* ] Correspondence

                Helen Morrison, Leibniz Institute on Aging ‐ Fritz Lipmann Institute, Beutenbergstraße 11, 07745 Jena, Germany.

                Email: helen.morrison@ 123456leibniz-fli.de

                Author information
                http://orcid.org/0000-0002-4337-4251
                http://orcid.org/0000-0003-0870-0696
                http://orcid.org/0000-0002-1992-4591
                Article
                ACEL12833
                10.1111/acel.12833
                6260910
                30168637
                79e90029-2fd5-4f68-bfc6-0c7f3a208385
                © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 October 2017
                : 14 June 2018
                : 21 July 2018
                Page count
                Figures: 7, Tables: 0, Pages: 15, Words: 7729
                Funding
                Funded by: Leibniz‐Gemeinschaft
                Award ID: SAW-2015-FLI-3
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: GRK1715/1
                Award ID: MO1421/2-1
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                acel12833
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.3 mode:remove_FC converted:28.11.2018

                Cell biology
                peripheral nervous system,inflammaging,neural regeneration,aging,macrophages,schwann cell
                Cell biology
                peripheral nervous system, inflammaging, neural regeneration, aging, macrophages, schwann cell

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